Bioabsorbable polyesteramides and uses thereof

ABSTRACT

Novel biodegradable polyesteramides derived from optionally functionalized diacids and optionally functionalized diamines or from compounds having both optionally functionalized acid and optionally functionalized amine moieties, their preparation, and absorbable surgical articles fabricated therefrom, such as monofilament and multifilament sutures, films, sheets, plates, clips, staples, pins, screws, stents, stent coatings, packaging materials, and other implantable surgical devices, and the like, are described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/053,950, filed May 16, 2008, the disclosure of which is herebyincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

Absorbable polyesteramides derived from optionally functionalizeddiacids and optionally functionalized diamines or from compounds havingboth optionally functionalized acid and optionally functionalized aminemoieties, their preparation, and absorbable surgical articles fabricatedtherefrom, such as monofilament and multifilament sutures, films,sheets, plates, clips, staples, pins, screws, stents, stent coatings,and the like, are described herein.

BACKGROUND OF THE INVENTION

Polyesteramides are polymers containing both ester linkages and amidelinkages. Their significance to the technology of medical devices stemsfrom the fact that the susceptibility of their ester linkages tohydrolysis confers upon them the ability to be eventually absorbed orresorbed by a body into which they have been implanted and their amidelinkages confer upon them the desirable mechanical propertiescharacteristic of polyamides.

Certain fiber-forming polyesteramides obtained from the single stagereaction of approximately equimolar amounts of a monoalkanolamine and adicarboxylic acid are described, for example, in U.S. Pat. No.2,386,454.

Other polyesteramides, disclosed in U.S. Pat. No. 4,226,243, have beenindicated to be useful for the manufacture of absorbable suture andother surgical devices. These polyesteramides are obtained from thereaction of a dicarboxylic acid ester with a bis-oxyamidodiol, thelatter of which is derived from the reaction of diethyl oxalate with amonoalkanolamine, such as ethanolamine.

U.S. Pat. No. 4,343,931 discloses absorbable surgical devicesmanufactured from polyesteramides which are obtained in a multi-stepprocess by first reacting a diamine with lactic or glycolic acid toproduce a diamidediol, and subsequently reacting the diamidediol with abischloroformate or a compound selected from the group consisting ofdicarboxylic acids, diacidchlorides, and dicarboxylic acid dianhydridesto provide the polyesteramide compounds.

U.S. Pat. No. 3,025,323 describes water-soluble amide diols derived fromlactone monomers and monoalkanol amines that may be used asintermediates in the preparation of polymers. These intermediates arealso disclosed as being useful as sizing additives for paper, leather,or other porous materials.

U.S. Pat. No. 6,120,788 describes fiber-forming bioabsorbablepolyesteramides made by the polymerization of diamide diols with3,6-dioxaoctanedioic acid. Certain of these polymers are said to beuseful for the production of surgical sutures having performancecharacteristics that may include low bending stiffness. They are alsodisclosed as being useful in the production of other fiber-basedbioabsorbable implants and molded devices.

U.S. Pat. No. 5,902,874 describes cyclic monomer derivedpolyesteramides, which are disclosed as being useful for manufactureinto shaped articles for use, for example, as surgical devices.

U.S. Pat. No. 5,914,387 describes shaped articles which are preparedfrom polyesteramides and which are disclosed as being useful as surgicaldevices. The disclosed polyesteramides have amino acid-derived groupsalternating with hydroxy acid-derived groups.

U.S. Pat. No. 5,919,893 describes polyesteramides which are disclosed asbeing suitable for use in biomedical applications and which may beobtained by reacting a diamino alkyl ester with an alpha-hydroxy acid toform a diamide diol which may be further reacted with an acyl halide ordicarboxylic acid to provide the polyesteramide.

Shaped articles made from nylon have been widely accepted for a varietyof applications, including some biomedical applications. Generallyspeaking, nylon refers to a family of high strength, resilient syntheticpolymeric materials containing recurring amide groups in the polymerbackbone. While nylon polymers have certain useful properties, shapedarticles based on nylon are not typically bioabsorbable and maytherefore be unacceptable in circumstances that require bioabsorption.For example, certain biomedical applications, such as surgical devicesincluding but not limited to monofilament and multifilament sutures,films, sheets, plates, clips, staples, pins, screws, stents, stentcoatings, and the like, require a material that is bioabsorbable.

In addition, high strength, highly flexible, tough, and durable fibersthat possess a prolonged flex fatigue life are needed for use asbraided, knitted, woven, or non-woven implants to augment and/ortemporarily reinforce autologous tissue grafts or to serve as scaffoldsfor tissue regeneration. One example of such an implant is known as aligament augmentation device (LAD) used to reconstruct the anteriorcruciate ligament (ACL) of the knee. Bioabsorbable fibers of the priorart, such as poly(L-lactic acid) (PLA), have not been successful in thisapplication due to low flex fatigue life, shedding of wear debris due tothe brittle nature of the fibers, and prolonged bioabsorption time.

Other well known uses for bioabsorbable polymers that have not beenfully realized or perfected with available polymers of the prior artinclude scaffolds for tissue engineering, bioabsorbable knitted vasculargrafts, drug-releasing devices, growth factor-releasing implants forbone and tissue regeneration, and fiber-reinforced composites fororthopedic applications. For example, composites of polymers reinforcedwith dissimilar materials, such as dissolvable glass fiber reinforcedpoly(lactic acid) are generally unacceptable for use as implants.Although dissolvable glass fibers provide high modulus needed for thecomposite to have high initial strength and stiffness, adhesion betweenglass and polymer may invariably fail prematurely in vivo resulting indevices with unacceptable in vivo performance.

Self-reinforced composites were developed as an alternative tocomposites of polymers reinforced with dissimilar materials, such asthose described above. In self-reinforced fiber composites, bothreinforcing fibers and matrix are generally made of the same material.Although the stiffness is lower than can be achieved with glass fibers,this alternative type of composite ensures good adhesion between fiberand matrix and thus may offer the possibility of longer lasting in vivostrength. Self-reinforced poly(glycolic acid) (PGA) rods, pins andscrews made by hot pressing or sintering PGA fibers have shown promisein clinical use. The main disadvantage of PGA in general is that ittypically degrades at too fast a rate for orthopedic applications andreleases an excessive concentration of acidic degradation products intothe surrounding tissue.

Despite advancements in the art of producing polymeric materials andmethods for making polymeric materials suitable for use in sutures,molded devices, and similar surgical articles, presently availablepolymers generally lack adequate performance properties desirable insurgical articles, for example, those related to bioabsorption, flexfatigue life, strength in use, flexibility and/or durability. Thus,there continues to be a need for new fibers that are monofilament, havehigh initial tensile knot strength, retain useful strength in vivo for aperiod of time, for example, about two weeks or longer, are fullybioabsorbed within a few months after strength loss, and have very lowbending stiffness. There is also a need for surgical article materialsthat have strength and resiliency characteristics comparable to that ofnylon, but which are also bioabsorbable. It would be particularlyadvantageous to provide surgical article materials having tunablephysical and/or biological properties, so that surgical articles havinga variety of end uses can be prepared. The present invention is relatedto these and other important ends.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed, in part, topolyesteramides which are derived from optionally functionalized diacidsand optionally functionalized diamines and which have tunable physicaland/or biological properties. In one embodiment, the polyesteramidescomprise Formula I:

—[(X—O—)_(a)—C(═O)—R¹—C(═O)—(O—Y)_(b)—(O—Y¹)_(b)—NH—R²—NH—(X¹—O—)_(a)]_(n)—  (I)

wherein:

-   -   each R¹ and R² is independently alkylene, cycloalkylenealkylene,        arylenealkylene, arylenealkylenearylene,        cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene, wherein:        -   (1) one or more of the —CH₂ 13 moieties in the alkylene            chain portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —O— or —S—; or        -   (2) one or more of the —CH₂—CH₂— moieties in the alkylene            chain portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —C(═O)—O— or —O—C(═O)—;    -   each X and X¹ is independently —C(═O)—CH(CH₃)—,        —C(═O)—(CH₂)_(y)— or —C(═O)—(CH₂CH₂O)_(z)—CH₂—;    -   each Y and Y¹ is independently —CH(CH₃)—C(═O)—,        —(CH₂)_(y)—C(═O)— or —(CH₂CH₂O)_(z)—CH₂—C(═O)—;    -   each a and b is independently an integer from about 1 to about        6;    -   each y and z is independently an integer from about 1 to about        24; and    -   n is an integer from about 5 to about 5000.

In another embodiment, the invention is directed to polyesteramidescomprising Formula IV:

—[—(X—O—_(a)—C(═O)—R¹—C(═O)—(O—Y)_(b)—NH—R²—NH—]_(n)—  (IV)

wherein:

-   -   each R¹ and R² is independently alkylene, cycloalkylenealkylene,        arylenealkylene, arylenealkylenearylene,        cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene, wherein:        -   (1) one or more of the —CH₂— moieties in the alkylene chain            portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —O— or —S—; or        -   (2) one or more of the —CH₂—CH₂— moieties in the alkylene            chain portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —C(═O)—O— or —O—C(═O)—;    -   each X is independently —C(═O)—CH(CH₃)—, —C(═O)—(CH₂)_(y)—, or        —C(═O)—(CH₂CH₂O)_(z)—CH₂—;    -   each Y is independently —CH(CH₃)—C(═O)—; —(CH₂)_(y)—C(═O)—; or        —(CH₂CH₂O)_(z)—CH₂—C(═O)—;    -   each a and b is independently an integer from about 2 to about        6;    -   each y and z is independently an integer from about 1 to about        24; and    -   n is an integer from about 5 to about 1000.

In yet another embodiment, the present invention is directed topolyesteramides comprising Formula VI:

—[C(═O)—R¹—C(═O)—(o—Y¹)_(b)—NH—R²—NH—(X¹—O—)_(a)—]_(n)—  VI

wherein:

-   -   each R¹ and R² is independently alkylene, cycloalkylenealkylene,        arylenealkylene, arylenealkylenearylene,        cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene, wherein:        -   (1) one or more of the —CH₂— moieties in the alkylene chain            portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —O— or —S—; or        -   (2) one or more of the —CH₂—CH₂— moieties in the alkylene            chain portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —C(═O)—O— or —O—C(═O)—;    -   each X¹ is independently —C(═O)—CH(CH₃)—, —C(═O)—(CH₂)_(y)—, or        —C(═O)—(CH₂CH₂O)_(Z)—CH₂—;    -   each Y¹ is independently —CH(CH₃)—C(═O)—, —(CH₂)_(y)—C(═O)—, or        —(CH₂CH₂O)_(z)—CH₂—C(═O)—;    -   each a and b is independently an integer from about 1 to about        6;    -   each y and z is independently an integer from about 1 to about        24; and    -   n is an integer from about 5 to about 5000.

The present invention is also directed, in part, to polyesteramideswhich are derived from compounds having both optionally functionalizedacid and optionally functionalized amine moieties and which have tunablephysical and/or biological properties. In certain embodiments, theinvention is directed to polyesteramides comprising Formula VIII:

—[(X—O—)_(a)—C(═O)—R⁵—NH—(X¹—O—)_(a)—]_(a)—  VIII

wherein:

-   -   each R⁵ is independently alkylene, cycloalkylenealkylene,        arylenealkylene, arylenealkylenearylene,        cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene, wherein:        -   (1) one or more of the —CH₂— moieties in the alkylene chain            portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —O— or —S—; or        -   (2) one or more of the —CH₂—CH₂— moieties in the alkylene            chain portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —C(═O)—O— or —O—C(═O)—;    -   each X and X¹ is independently —C(═O)—CH(CH₃)—,        —C(═O)—(CH₂)_(y)—, or —C(═O)—(CH₂CH₂O)_(z)—CH₂—;        (CH₂CH₂O)_(z)—CH₂—;    -   each a is independently an integer from about 1 to about 6;    -   each y and z is independently an integer from about 1 to about        24; and    -   n is an integer from about 5 to about 5000.

In yet another embodiment, the invention relates to polyesteramidescomprising Formula XI:

—[—C(═O)—CH₂—O—CH₂—C(═O)—O—Ar—O—C(═O)—CH₂—O—CH₂C(═O)—NH—R²—NH]_(n)—  XI

wherein:

-   -   each Ar is arylene;    -   each R² is independently alkylene, cycloalkylenealkylene,        arylenealkylene, arylenealkylenearylene,        cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene, wherein:        -   (1) one or more of the —CH₂— moieties in the alkylene chain            portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —O— or —S—; or    -   (2) one or more of the —CH₂—CH₂— moieties in the alkylene chain        portion of an alkylene, cycloalkylenealkylene, arylenealkylene,        arylenealkylenearylene, cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene moiety are optionally replaced by        —C(═O)—O— or —O—C(═O)—; and    -   n is an integer from about 5 to about 5000.

In still another embodiment, the invention is directed topolyesteramides comprising: a polymer wherein:

-   -   one or more of the amido linkages in the polymer backbone are        replaced with —[C(═O)—(O—X¹)_(a)—N]— linkages; or    -   one or more of the ester linkages in the polymer backbone are        replaced with —[C(═O)—(O—X²)_(b)O]— linkages;    -   wherein:        -   each X¹ and each X² is independently chosen from:            —CH(CH₃)—C(═O)—, —(CH₂)_(y)—C(═O)— or            —(CH₂CH₂O)_(Z)—CH₂—C(═O)—; and        -   each a and each b is independently an integer from 1 to            about 24, provided that at least one a or at least one b is            an integer from 2 to about 24.

In another embodiment, the invention is directed to surgical articles,coatings for stents, delivery systems for one or more biologically orpharmacologically active agents, and/or biodegradable packagingmaterials, each comprising the polyesteramides of the present inventionas disclosed herein.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention relates to the discovery of new biodegradablepolyesteramides. In certain embodiments, the polyesteramides are derivedfrom functionalized diacids and/or functionalized aliphatic diamines. Inother embodiments, the polyesteramides are derived from monomers havingoptionally functionalized acid and optionally functionalized aminemoieties.

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

As used herein, “alkyl” refers to an optionally substituted, saturatedstraight, or branched hydrocarbon moiety having from about 1 to about 20carbon atoms (and all combinations and subcombinations of ranges ofcarbon atoms and specific numbers of carbon atoms therein), preferablywith from about 1 to about 8 carbon atoms, herein referred to as “loweralkyl”, more preferably from about 1 to about 3 carbon atoms, withmethyl being even more preferred. Alkyl groups include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl,3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

As used herein, the term “aryl” refers to an optionally substituted,mono-, di-, tri-, or other multicyclic aromatic ring system moietyhaving from about 6 to about 50 carbon atoms (and all combinations andsubcombinations of ranges of carbon atoms and specific numbers of carbonatoms therein), preferably with from about 6 to about 10 carbons, withabout 6 carbon atoms being preferred. Non-limiting examples include, forexample, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

As used herein, the term “cycloalkyl” refers to an optionallysubstituted, mono-, di-, tri-, or other multicyclic alicyclic ringsystem moiety having from about 3 to about 20 carbon atoms (and allcombinations and subcombinations of ranges of carbon atoms and specificnumbers of carbon atoms therein). In some preferred embodiments, thecycloalkyl groups have from about 3 to about 8 carbon atoms, morepreferably from about 3 to about 6 carbon atoms. Multi-ring structuresmay be bridged or fused ring structures, wherein the additional groupsfused or bridged to the cycloalkyl ring may include optionallysubstituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl rings.Exemplary cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, adamantyl,2-[4-isopropyl-1-methyl-7-oxa-bicyclo[2.2.1]heptanyl], and2-[1,2,3,4-tetrahydro-naphthalenyl].

As used herein, “alkylene” refers to a bivalent alkyl moiety having thegeneral formula —(CH₂)_(n)—, where n is from about 1 to about 150,preferably about 1 to about 20, more preferably about 1 to about 16,with about 1 to about 10 being even more preferred. By bivalent, it ismeant that the group has two open sites each of which bonds to anothergroup. Non-limiting examples include methylene, ethylene, trimethylene,pentamethylene, and hexamethylene. Alkylene groups can be optionallysubstituted with alkyl, wherein alkyl is as previously defined. The term“lower alkylene” herein refers to those alkylene groups having fromabout 1 to about 6 carbon atoms.

As used herein, “arylene” refers to a bivalent aryl moiety, wherein arylis as previously defined. The ring system may be monocyclic or fusedpolycyclic (e.g., bicyclic, tricyclic, etc.). A C₆ ring system, i.e., aphenylene ring, is a preferred aryl group. In various embodiments, thebivalent C₆aryl moiety may be a 1,2-, 1,3-, or 1,4-bivalent aryl moiety.

As used herein, “cycloalkylene” refers to a bivalent cycloalkyl moiety,wherein cycloalkyl is as previously defined. Cycloalkylene is a type ofalkylene group which is a cycloalkyl group with two open bonding sites.

As used herein, “cycloalkylenealkylene” refers to a bivalent moiety,wherein a cycloalkylene group is bonded to a non-cyclic alkylene group,wherein each of the cycloalkylene and non-cyclic alkylene groups has oneopen bonding site, and wherein cycloalkylene and alkylene are each aspreviously defined. “Cycloalkylenealkylene” includes moieties having-cycloalkylene-alkylene- and -alkylene-cycloalkylene- bonding orders orconfigurations.

As used herein, “arylenealkylene” refers to a bivalent moiety, whereinan arylene group is bonded to a non-cyclic alkylene group, and each ofthe arylene and non-cyclic alkylene group has one open bonding site,wherein arylene and alkylene are each as previously defined.“Arylenealkylene” includes moieties having -arylene-alkylene- and-alkylene-arylene- bonding orders or configurations.

As used herein, “arylenealkylenearylene” refers to bivalent moieties,wherein two arylene groups are bonded to a non-cyclic alkylene group,and each of the arylene groups has one open bonding site, whereinarylene and alkylene are each as previously defined.

As used herein, “cycloalkylenealkylenecycloalkylene” refers to abivalent moiety, wherein two cycloalkylene groups are bonded to anon-cyclic alkylene group, and each of the cycloalkylene groups has oneopen bonding site, wherein cycloalkylene and alkylene are each aspreviously defined.

As used herein, “arylenealkylenecycloalkylene” refers to a bivalentmoiety, wherein an arylene and a cycloalkylene group are each bonded toa non-cyclic alkylene group, and each of the arylene and cycloalkylenegroups has one open bonding site, wherein arylene, cycloalkylene, andalkylene are as previously defined. “Arylenealkylenecycloalkylene”includes moieties having -arylene-alkylene-cycloalkylene- andcycloalkylene-alkylene-arylene- bonding orders or configurations.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. Within the context of the present invention, compoundsare stable if they do not degrade significantly prior to their intendeduse under normal conditions. In some instances, compounds of theinvention are may be designed or required to be bioabsorbed orbiodegraded as part of their intended function. Bioabsorbability and/orbiodegradability, which may be an advantageous property of the presentpolymers, is not intended to mean that the polymeric compound areunstable.

It is believed the chemical formulas and names used herein correctly andaccurately reflect the underlying chemical compounds. However, thenature and value of the present invention does not depend upon thetheoretical correctness of these formulae, in whole or in part. Thus itis understood that the formulas used herein, as well as the chemicalnames attributed to the correspondingly indicated compounds, are notintended to limit the invention in any way, including restricting it toany specific tautomeric form, except where such limit is clearlydefined.

Accordingly, in one embodiment of the present invention, there areprovided polyesteramides comprising Formula I:

—[(X—O—)_(a)—C(═O)—R¹—C(═O)—(O—Y)_(b)—(O—Y¹)_(b)—NH—R²—NH—(X¹—O—)_(a)]_(n)—  (I)ps

wherein:

-   -   each R¹ and R² is independently alkylene, cycloalkylenealkylene,        arylenealkylene, arylenealkylenearylene,        cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene, wherein:        -   (1) one or more of the —CH₂— moieties in the alkylene chain            portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —O— or —S—; or        -   (2) one or more of the —CH₂—CH₂— moieties in the alkylene            chain portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —C(═O)—O— or —O—C(═O)—;    -   each X and X¹ is independently —C(═O)—CH(CH₃)—,        —C(═O)—(CH₂)_(y)— or —C(═O)—(CH₂CH₂O)_(z)—CH₂—;    -   each Y and Y¹ is independently —CH(CH₃)—C(═O)—,        —(CH₂)_(y)—C(═O)— or —(CH₂CH₂O)_(Z)—CH₂—C(═O)—;    -   each a and b is independently an integer from about 1 to about        6;    -   each y and z is independently an integer from about 1 to about        24; and    -   n is an integer from about 5 to about 5000.

In certain preferred embodiments, the polyesteramides comprising FormulaI may be prepared by the condensation polymerization of functionalizeddiacids of Formula II and functionalized diamines of Formula III asshown below:

HO—(X—O—)_(a)—C)═O)—R¹—C(═O)—(O—Y)_(b)—OH;  II

and

R³—Y¹—(—O—Y¹)_(b-1)—NH—R²—NH—(X¹—O)_(a-1)—(X¹)—R⁴  III

wherein r¹, R², X, X¹, Y, Y¹, a and b are each as defined above, and R³and R⁴ are independently selected from Cl, F, Br, and I. Suitableexamples of diacids of general Formula II which can be used in thepresent invention include but are not limited to the following:

In another embodiment, the present invention provides polyesteramidescomprising Formula IV:

—[—(X—O—)_(a)—C(═O)—R¹—C(═O)—(O—Y)_(b)—NH—R²—NH—]_(n)—  IV

wherein:

-   -   each R¹ and R² is independently alkylene, cycloalkylenealkylene,        arylenealkylene, arylenealkylenearylene,        cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene, wherein:        -   (1) one or more of the —CH₂— moieties in the alkylene chain            portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —O— or —S—; or        -   (2) one or more of the —CH₂—CH₂— moieties in the alkylene            chain portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —C(═O)—O— or —O—C(═O)—;    -   each X is independently —C(═O—CH(CH₃)—, —C(═O)—(CH₂)_(y)—, or        —C(═O)—(CH₂CH₂O)_(z)—CH₂—;    -   each Y is independently —CH(CH₃)—C(═O)—, —(CH₂)_(y)—C(═O)—, or        —(CH₂CH₂O)_(z)—CH₂—C(═O)—;    -   each a and b is independently an integer from about 2 to about        6;    -   each y and z is independently an integer from about 1 to about        24; and    -   n is an integer from about 5 to about 5000.

In certain preferred embodiments, the polyesteramides comprising FormulaIV may be prepared by the condensation polymerization of functionalizeddiacids of Formula II and diamines of Formula V as shown below:

HO—(X—O—)_(a)—C(═O)—R¹—C(═))—O—Y)_(b)—OH  II

NH₂—R²—NH₂  V

wherein R₁, R₂, X, Y, a and b are each as defined above.

In yet another embodiment the present invention provides polyesteramidescomprising Formula VI:

—[C(═O)—R¹—C(═O)—(O—Y¹)_(b)—NH—R²—NH—(X¹—I—)_(a)—]_(n)—;  VI

wherein:

-   -   each R¹ and R² is independently alkylene, cycloalkylenealkylene,        arylenealkylene, arylenealkylenearylene,        cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene, wherein:        -   (1) one or more of the —CH₂— moieties in the alkylene chain            portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —O— or —S—; or        -   (2) one or more of the —CH₂—CH₂— moieties in the alkylene            chain portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —C(═O)—O— or —O—C(═O)—;    -   each X¹ is independently —C(═O)—CH(CH₃)—C(═O)—,        —(CH₂)_(y)—C(═O)—, or —C(═O)—(CH₂CH₂O)_(z)—CH₂—    -   each Y¹ is independently —CH(CH₃)—C(═O)—, —(CH₂)_(y)—C(═O)—, or        —(CH₂CH₂O)_(z)—CH₂—C(═O)—;    -   each a and b is independently an integer from about 1 to about        6;    -   each y and z is independently an integer from about 1 to about        24; and    -   n is an integer from about 5 to about 5000.

In some preferred embodiments, polyesteramides comprising Formula VI maybe prepared by the condensation polymerization of diacids of Formula VIIand functionalized diamines of Formula III as shown below:

HOOC—R¹—COOH  VII

R³—Y¹—(—O—Y¹)_(b-1)—NH—R²—NH—(X¹—O)_(a-1)—(X¹)—R⁴  III

wherein R¹, R², X¹, Y¹, a and b are each as indicated hereinabove; andR³ and R⁴ are independently selected from Cl, F, Br, and I.

In some preferred embodiments, the polyesteramides comprising Formula I,IV, or VI have the following formula:

wherein n is as previously defined.

In other preferred embodiments, the polyesteramides comprising FormulaI, IV, or VI have the following formula:

wherein n is as previously defined.

In yet another embodiment the present invention provides polyesteramidescomprising:

-   -   a polymer wherein:        -   one or more of the amido linkages in the polymer backbone            are replaced with —[C(═O)—(O—X¹)_(a)—N]— linkages; or        -   one or more of the ester linkages in the polymer backbone            are replaced with —[C(═O)—(O—X²)_(b)—O]— linkages;            wherein:            -   each X¹ and each X² is independently selected from:                —CH(CH₃)—C(═O)—, —(CH₂)_(y)—C(═O)— and                —(CH₂CH₂O)_(z)—CH₂—C(═O)—; and            -   each a and each b is independently an integer from 1 to                about 24, provided that at least one a or at least one b                is an integer from 2 to about 24. Preferably, one or                more of the amido linkages in the polymer backbone are                replaced with —[C(═O)—(O—X¹)_(a)—N]— linkages; and one                or more of the ester linkages in the polymer backbone                are replaced with —[C(═O)—(O—X²)_(b)—O]— linkages.                Alternatively preferred polyesteramides contain one or                more ester linkages in the polymer backbone replaced                with —[C(═O)—(O—X²)_(b)—O]— linkages, wherein each a and                each b is independently an integer from 1 to about 12,                more preferably 1 to about 6, with from 1 to about 3                being even more preferred. Other alternatively preferred                polyesteramides contain one or more amido linkages in                the polymer backbone replaced with                —[C(═O)—(O—X¹)_(a)—N]— linkages, wherein each a and each                b is independently an integer from 1 to about 12, more                preferably 1 to about 6, with from 1 to about 3 being                even more preferred.

Suitable examples of diacids of general Formula VII which may be usefulin the preparation of the polyesteramides of the present inventioninclude but are not limited to the following:

In certain preferred embodiments of polyesteramides comprising FormulaI, IV, or VI, R¹ is alkylene, preferably C₁-C₆₀, more preferably C₁-C₂₀,even more preferably C₁-C₁₆, still more preferably C₁-C₁₂, yet morepreferably C₃-C₉alkylene. Alternatively, the alkylene is preferably C₃,C₆, C₇, C₉, or C₁₆alkylene. Also in preferred embodiments, alkylene isunsubstituted or substituted with alkyl, preferably C₁-C₃alkyl, morepreferably methyl. In other preferred embodiments wherein one or more—(CH₂)— moieties in the alkylene chain portion of R¹ are replaced with aheteroatom, preferably —O— or —S—, with —O— being more preferred.Preferably, one or more —(CH₂)— moieties in the alkylene chain portionof R¹ are replaced with from about 1 to about 50 —O— or —S— atoms, morepreferably from about 10 to about 50 —O— or —S— atoms. In otheralternative embodiments, wherein one or more —(CH₂)— moieties in thealkylene chain portion of R¹ are replaced, they are preferably replacedwith from about 1 to about 10 —O— or —S— atoms, more preferably fromabout 1 to about 5 —O— or —S— atoms, still more preferably from about 1to about 3 —O— or —S— atoms.

In other preferred embodiments of polyesteramides comprising Formula I,IV, or VI, wherein R¹ is alkylene and one or more —(CH₂CH₂)— moieties inthe alkylene chain portion of R¹ are replaced, they are preferablyreplaced with from about 1 to about 10 —O—C(═O)— or —C(═O)—O— moieties,more preferably from about 1 to about 8 —O—C(═O)— or —C(═O)—O— moieties,still more preferably from about 2 to about 6 —O—C(═O)— or —C(═O)—O—moieties.

In certain preferred embodiments of polyesteramides comprising FormulaI, IV, or VI, R² is alkylene or arylenealkylenecycloalkylene, morepreferably arylenealkylenecycloalkylene. In embodiments wherein R² isalkylene, the alkylene is preferably C₁-C₁₅₀, more preferably C₅-C₅₀,still more preferably C₁₀-C₂₀, still more preferably C₁₀-C₁₈, yet morepreferably C₁₀-C₁₄alkylene. In some more preferred embodiments, thealkylene is unsubstituted or substituted with alkyl, preferablyC₁-C₃alkyl, more preferably methyl. In other preferred embodimentswherein one or more —(CH₂)— moieties in the alkylene chain portion of R²are replaced with a heteroatom, such as —O— or —S—, preferably —O—, theyare preferably replaced with from about 1 to about 50 —O— or —S— atoms,more preferably from about 10 to about 50 —O— or —S— atoms. In otheralternative embodiments, wherein one or more —(CH₂)— moieties in thealkylene chain portion of R⁵ are replaced with —O— or —S— atoms,preferably —O— atoms, they are preferably replaced with from about 1 toabout 10 —O— or —S— atoms, more preferably from about 1 to about 5 —O—or —S— atoms, still more preferably from about 1 to about 3 —O— or —S—atoms.

In other preferred embodiments of polyesteramides comprising Formula I,IV, or VI, wherein R² is alkylene and one or more —(CH₂CH₂)— moieties inthe alkylene chain portion of R² are replaced, they are preferablyreplaced with from about 1 to about 10 —O—C(═O)— or —C(═O)—O— moieties,more preferably from about 1 to about 8, still more preferably fromabout 2 to about 6 —O—C(═O)— or—C(═O)—O— moieties.

In certain preferred embodiments of polyesteramides comprising FormulasI, IV, VI or VIII or intermediates thereof comprising Formulas II, IIIor IX, each X and/or X¹ are independently —C(═O)—CH(CH₃)— or—C(═O)—(CH₂)_(y)—. In other preferred embodiments; each X and/or X¹ isindependently —C(═O)—(CH₂CH₂O)_(z)—CH₂—. Alternatively preferred, each Xand/or X¹ is independently —C(═O)—CH(CH₃)—, —C(═O)—(CH₂)—,—C(═O)—(CH₂)₅—, or —C(═O)—CH₂CH₂OCH₂—.

In other preferred embodiments of polyesteramides comprising Formulas I,IV, or VI or intermediates thereof comprising Formulas II or III, each Yand/or Y¹ is independently —CH(CH₃)—C(═O)—, —(CH₂)_(y)—C(═O)—. In otherpreferred embodiments; each Y and/or Y¹ is independently—(CH₂CH₂O)_(z)—CH₂—C(═O)—. Alternatively preferred, each Y and/or Y¹ isindependently —CH(CH₃)—C(═O)—, —(CH₂)—C(═O)—, —CH₂)₅—C(═O)—or—CH₂CH₂O—CH₂—C(═O)—.

In certain preferred embodiments of polyesteramides comprising FormulaVIII or intermediates thereof comprising Formula IX, R⁵ is alkylene orarylenealkylenearylalkylene. In embodiments wherein R⁵ is alkylene orcontains an alkylene moiety, such as in the grouparylenealkylenearylalkylene, the alkylene or alkylene portion ispreferably C₁-C₁₅₀, more preferably C₅-C₅₀, still more preferablyC₁₀-C₂₀, still more preferably C₁₀-C₁₈, yet more preferablyC₁₀-C₁₄alkylene. In some more preferred embodiments, the alkyleneportion is unsubstituted or substituted with alkyl, preferablyC₁-C₃alkyl, more preferably methyl. In other preferred embodimentswherein one or more —(CH₂)— moieties in the alkylene chain portion of R⁵are replaced, they are preferably replaced with one or more heteroatoms,for example —O—or —S—, preferably —O—, with about 1 to about 50 —O—atoms being preferred, more preferably from about 10 to about 50 —O—atoms. In other alternative embodiments, wherein one or more —(CH₂)—moieties in the alkylene chain portion of R⁵ are replaced, they arepreferably replaced with from about 1 to about 10 —O— atoms, morepreferably from about 1 to about 5, still more preferably from about 1to about 3 —O— atoms.

In other preferred embodiments of polyesteramides comprising FormulaVIII or intermediates thereof comprising Formula IX, wherein R⁵ isalkylene and one or more —(CH₂CH₂)— moieties in the alkylene chainportion of R⁵ are replaced, they are preferably replaced with from about1 to about 10 —O—C(═O)— or —C(═O)—O— moieties, more preferably fromabout 1 to about 8 —O—C(═O)— or —C(═O)—O— moieties, still morepreferably from about 2 to about 6 —O—C(═O)— or —C(═O)—O— moieties.

In preferred embodiments of polyesteramides comprising Formula VIII orintermediates thereof comprising Formula IX, wherein R⁵ contains anarylene portion, such as in the group arylenealkylenearylalkylene , thearylene portion is preferably C₆arylene.

In other preferred embodiments of polyesteramides comprising Formula I,IV, VI or VIII or intermediates thereof comprising Formula II, III orIX, each a and b is independently an integer from about 1 to about 12,more preferably from about 2 to about 12. Alternatively preferred, eacha and b is independently an integer from about 1 to about 6, morepreferably from about 2 to about 6. In still other preferredembodiments, each a and b is independently an integer from about 1 toabout 3, more preferably from about 2 to about 3.

In some preferred embodiments of polyesteramides comprising Formula I,IV, VI or VIII or intermediates thereof comprising Formula II, III orIX, each y and z is independently an integer from about 1 to about 24,more preferably from about 1 to about 18, still more preferably fromabout 1 to about 12, yet more preferably from about 1 to about 8, evenmore preferably from about 1 to about 6. In certain alternativelypreferred embodiments, each y and z is independently 1 or 5.

In other preferred embodiments of polyesteramides comprising Formula I,IV, VI, or VIII, n is an integer from about 5 to about 100, morepreferably from about 10 to about 50. In certain alternativeembodiments, n is an integer from about 5 to about 5000, more preferablyfrom 10 to 3000, still more preferably from 20 to 1000.

In certain embodiments of the invention, polyesteramides comprisingFormula I may be prepared by a process that comprises contacting acompound of Formula II:

HO—(—X—O—)₁—C(═O)—R¹—C(═O)—(O—Y)_(b)—OH  II

with a compound of Formula III:

R³—Y¹—(—O—Y¹)_(b-1)—NH—R²—NH—(X¹—O)_(a-1)—(X¹)—R⁴  III

wherein R¹, R², X, X¹, Y, and Y¹, a and b are each as defined above; andR³ and R⁴ are independently selected from Cl, F, Br, and I;

-   -   for a time and under conditions effective to provide the        polyesteramide of Formula I.

In certain embodiments of the invention, polyesteramides comprisingFormula IV may be prepared by a process that comprises contacting acompound of Formula II:

HO—(X—O—)_(a)—C(═O)—R¹—C(═O)—(O—Y)_(b)—OH  II

with a compound of Formula V:

NH₂—R²—NH₂  V

wherein R₁, R₂, X, Y, a and b are each as defined above;

-   -   for a time and under conditions effective to provide the        polyesteramide of Formula IV.

In certain embodiments of the invention, polyesteramides comprisingFormula VI may be provided by a process that comprises contacting acompound of Formula VII:

HOOC—R¹—COOH  VII

with a compound of Formula III:

R³—Y^(Y) ¹—(—O—Y¹)_(b-1)—NH—R²—NH—(X¹—O)_(a-1)—(X¹)—R⁴  III

wherein R¹, R², X¹, Y¹, a and b are each as defined above; and R³ and R⁴are independently selected from Cl, F, Br, and I;

-   -   for a time and under conditions effective to provide the        polyesteramide of Formula VI.

In certain embodiments of the invention, polyesteramides comprisingFormula VIII may be prepared by a process that comprises contacting acompound of Formula IX:

H—O—(X—O—)_(a)—C(═O)—R⁵—NH—(X¹—O)_(a-1)—(X¹)—R⁶  IX

with a compound of Formula IX:

H—O—(X—O—)_(a)—C(═O)—R⁵—NH—(X¹—O)_(a-1)—(X¹)—R⁶  IX

wherein R⁵, X, X¹, and a are each as indicated hereinabove; and R⁶ isCl, F, Br, or I; for a time and under conditions effective to providethe polyesteramide of Formula VIII.

In yet another embodiment, the present invention provides biodegradablepolyesteramides comprising Formula VIII:

—[(X—O—)_(a)—C(═O)—R⁵—NH—(X¹—O—)_(a)—]_(n)—  VIII

wherein:

-   -   each R⁵ is independently alkylene, cycloalkylenealkylene,        arylenealkylene, arylenealkylenearylene,        cycloalkylenealkylenecycloalkylene, or        arylenealkylenecycloalkylene, wherein:        -   (1) one or more of the —CH₂— moieties in the alkylene chain            portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —O— or —S—; or        -   (2) one or more of the —CH₂—CH₂— moieties in the alkylene            chain portion of an alkylene, cycloalkylenealkylene,            arylenealkylene, arylenealkylenearylene,            cycloalkylenealkylenecycloalkylene, or            arylenealkylenecycloalkylene moiety are optionally replaced            by —C(═O)—O— or —O—C(═O)—;    -   each X and X¹ is independently —C(═O)—CH(CH₃)—, or        —C(═O)—(CH₂CH₂O)_(z)—CH₂—;    -   each a is independently an integer from about 1 to about 6;    -   each y and z is independently an integer from about 1 to about        24; and    -   n is an integer from about 5 to about 5000.

It would be readily apparent to one of ordinary skill in the art oncearmed with the teachings in the present application that the termini inany of the polyesteramides of the present invention may be determined,in part, by the ratio of reactants employed in preparation of thepolyesteramide. It would also be apparent to the ordinarily skilledartisan that the terminal groups for a given polyesteramide may bederivatized by further reacting the polyesteramide with additionalderivatizing agents.

In certain preferred embodiments, polyesteramides of Formula VIII areprepared by self-condensation polymerization of amino acids of Formula(IX):

H—O—(X—O—)_(a)—C(═O)—R⁵—NH—(X¹—O)_(a-1)—(X¹)—R⁶  IX

wherein R⁵, X, X¹, and a are each as indicated hereinabove; and R⁶ isCl, F, Br, or I.

Alternatively, the polyesteramides of Formula VIII are prepared byself-condensation polymerization of amino acids of Formula (IXa):

H—O—C(═O)—R⁵—NH—(X¹—O)_(a)—(X—O—)_(a-1)—(X)—R⁶;  IXa

or by self-condensation polymerization of amino acids of Formula (IXb):

R⁶—C(═O)—R⁵—NH—(X¹—O)₁—(X—O—)_(a-1)—(X)—O—H;  IXa

In some embodiments, polyesteramides are provided that are in partderived from a compound of Formula XI:

HO—C(═O)—CH₂—O—CH₂—C(═O)—O—Ar—O—C(═O)—CH₂—O—CH₂C(═O)—OH;  XI

wherein Ar is an arylene moiety that is derived from an aryl-containingcompound in which the aryl group is substituted with two hydroxylgroups. In some preferred embodiments, the diacid subunits are derivedfrom diacids prepared by ring opening of diglycolic anhydride with adihydroxy substituted aryl compound, more preferably a dihydroxysubstituted aryl compound selected from the group consisting of naturalproducts such as flavonoids, coumarins, chalcones, acetophenones, orbenzophenones, each having the required hydroxy substituents.Non-limiting examples include quercetin, quercetrin, epicatechin,catechin, hesperetin, kaempherol, anthocyanidine, rutin, myricetin,fisetin, isoquercitrin, rhamnetin, and other compounds with at least onedihydroxy substituted aryl subunit. In alternatively preferredembodiments, amino acids such as tyrosine, as well as drugs and/orbiologically active compounds may also be used to provide the diacidsvia opening of the diglycolic anhydride, so long as they contain an arylgroup with the required hydroxyl substituents thereon. Otherdihydroxy-substituted aryl compounds in addition to those exemplifiedabove would be apparent to one of ordinary skill in the art, once armedwith the teachings in the present application.

Suitable diamines of general Formula V which can be used in the presentinvention include but are not limited to polyethyleneimines,polyoxypropylenediamines available under the tradename JEFFAMINES(Huntsman Corporation, Houston, Tex.), spermine, spermidine,hexamethylenediamine, octamethylenediamine, decamethylene diamine,dodecamethylene diamine, hexadecamethylene diamine, octadecamethylenediamine, polyamidoamine dendrimers, dextrans, PEG-dextran conjugates,cysteines, proteins containing amines, and hydrolysable diamines havingthe following formulas.

Suitable examples of functionalized diamines of Formula III that can beused in the present invention include but are not limited to thefollowing formulas.

wherein X is OH, F, Cl, Br or I and n is as previously defined.

The processes and synthetic methods described hereinthroughout may becarried out in any suitable solvent. Generally, suitable solvents aresolvents which are substantially non-reactive with the startingmaterials (reactants), the intermediates, or products at thetemperatures at which the reactions are carried out, i.e., temperatureswhich may range from the solvent's freezing temperature to the solvent'sboiling temperature, and in which the product polyesteramides aresoluble. A given reaction may be carried out in one solvent or a mixtureof more than one solvent. Exemplary solvents useful in the preparationof polyesteramides of Formulas I, IV, VI, and/or VIII includehalogenated solvents, preferably halogenated aromatic solvents, morepreferably halogenated benzene solvent, with chlorobenzene even morepreferred.

One preferred embodiment of the present invention relates tobioabsorbable polyesteramides having certain nylon-like properties.Preferably the polyesteramides are formed by the condensationpolymerization of tetraglycolic acid functionalized adipic acid withtetraglycolic acid functionalized hexamethylene diamine as shown below:

n is an integer from about 5 to about 5000, more preferably from about10 to about 3000, still more preferably from about 20 to about 1000.

In certain preferred embodiments of polyesteramides comprising FormulasI, IV, VI, or VIII, the polyesteramide is further polymerized with alactone monomer, preferably selected from the group consisting ofglycolide, lactide, E-caprolactone, trimethylene carbonate, andp-dioxanone. In certain preferred embodiments, the surgical articles orbiodegradable packing materials of the present invention comprise thesefurther polymerized polyesteramides.

In preferred form, the polyesteramides described herein arebiodegradable and in certain aspects biocompatible and suitable for usein medicine. Such polyesteramides combine the good mechanical propertiesof polyamides with the degradability of polyesters.

The degradable polyesteramide herein is suitable for use in a widevariety of applications. Since the degradation products of thebiocompatible polyesteramides described herein are non-toxic, they areadvantageously suitable for biomedical uses. For example, the propertiesof the polymer may be tunable, i.e., they may be made to degrade moreslowly or more quickly by reducing or increasing respectively the numberof ester linkages in the polymeric chain, and can thus be utilized forfabricating short-term or long-term implantable surgical materials.

The polyesteramides may be formed into surgical articles using any knowtechnique, such as, for example, extrusion, molding and/or solventcasting. The polyesteramides may be used alone, blended with otherabsorbable compositions, or in combination with nonabsorbablecomponents. A wide variety of surgical articles may be manufactured fromthe polyesteramides described herein. These include but are not limitedto clips and other fasteners, staples, sutures, pins, screws, prostheticdevices, wound dressings, drug delivery devices, anastomosis rings, andother implantable devices. Examples of implants include prostheticdevices, sutures, staples, clips and other fasteners, screws, pins,films, meshes, drug delivery devices or systems, anastomosis rings,surgical dressings and the like. In certain preferred drug deliverysystems, the systems comprise a polyesteramide of Formula I, IV, VI, orVIII in admixture with a biologically or pharmaceutically active agent.Other preferred uses of the surgical article include their use as ascaffold for tissue engineering comprising a porous structure for theattachment and proliferation of cells. The polyesteramides herein mayalso be used to fabricate degradable containers and packaging materialswhich can degrade in landfills in contrast to existing non-degradablematerials which present environmental concerns.

Fibers made from the present polyesteramides can be knitted or wovenwith other fibers, either absorbable or nonabsorbable to form meshes orfabrics. Compositions including these polyesteramides may also be usedas an absorbable coating for surgical devices.

Optional additives which may be present in compositions made from thepolyesteramides described herein include plasticizers, release agentsand other processing aids. Where the composition is used to make asurgical device, stearic acid or calcium stearate are particularlyuseful additives due to their biocompatiblity.

In another aspect, the compositions containing the polyesteramidesdescribed herein can be used to make reinforced composites. Thus, forexample, the polyesteramide composition can form the matrix of thecomposite and can be reinforced with bioabsorbable or nonabsorbablefibers or particles. Alternatively, a matrix of any bioabsorbable ornon-bioabsorbable polymer composition can be reinforced with fibers orparticulate material made from compositions containing thepolyesteramides described herein.

In an alternative embodiment, the polyesteramides described herein maybe admixed with a filler. The filler may be in any particulate form,including granulate and staple fibers.

While any known filler may be used, hydroxyapatite, tricalciumphosphate, bioglass or other bioceramics are the preferred fillers.Normally, from about 10 grams to about 400 grams of filler are mixedwith 100 grams of polymer. The filled, cross-linked polymers are useful,for example, as a molding composition.

It is further contemplated that one or more medico-surgically usefulsubstances can be incorporated into compositions containing thepolyesteramides described herein. Examples of such medico-surgicallyuseful substances include, for example, those which accelerate orbeneficially modify the healing process when particles are applied to asurgical repair site. For example, articles made from compositionscontaining the present polyesteramides may carry a therapeutic agentwhich will be deposited at the repair site. The therapeutic agent may bechosen for its antimicrobial properties, capability for promoting repairor reconstruction and/or new tissue growth. Antimicrobial agents such asbroad spectrum antibiotic, for example, gentamycin sulfate, erythromycinor derivatized glycopeptides which are slowly released into the tissuemay be applied in this manner to aid in combating clinical andsub-clinical infections in a tissue repair site. To promote repairand/or tissue growth, one or several growth promoting factors may beintroduced into the articles, e.g., fibroblast growth factor, bonegrowth factor, epidermal growth factor, platelet derived growth factor,macrophage derived growth factor, alveolar derived growth factor,monocyte derived growth factor, magainin, and the like. Some therapeuticindications are: glycerol with tissue or kidney plasminogen activator tocause thrombosis, superoxide dimutase to scavenge tissue damaging freeradicals, tumor necrosis factor for cancer therapy or colony stimulatingfactor and interferon, interleukin-2 or other lymphokine to enhance theimmune system.

It is contemplated that it may be desirable to dye articles made fromcompositions containing the present polyesteramides in order to increasevisibility of the article in the surgical field. Dyes, such as thoseknown to be suitable for incorporation in sutures, may be used. Suchdyes include but are not limited to carbon black, bone black, D&C GreenNo. 6, and D&C Violet No. 2 as described in the handbook of U.S.Colorants for Food, Drugs and Cosmetics by Daniel M. Marrion (1979).Preferably, articles in accordance with this disclosure are dyed byadding up to about a few percent and preferably about 0.2% dye to theresin composition prior to extrusion.

The compounds employed in the methods of the present invention may beprepared in a number of ways well known to those skilled in the art. Thecompounds may be synthesized, for example, by the methods describedbelow, or variations thereon as appreciated by the skilled artisan. Allprocesses disclosed in association with the present invention arecontemplated to be practiced on any scale, including milligram, gram,multigram, kilogram, multikilogram or commercial industrial scale.

The following examples are included to further illustrate the inventionand are not to be considered as limiting the invention anyway.

EXAMPLES Example 1 Synthesis of Benzylacetate Functionalized Adipic Acid

Into an oven-dried 250 ml round-bottomed flask under a nitrogenatmosphere at room temperature were added with stifling 50 grams (342mmol) of adipic acid, 500 ml of acetone and 143 ml of triethylamine. Tothis solution stifling at room temperature was added dropwise 145 grams(785 mmol) of benzyl chloroacetate. The reaction mixture was stirredovernight at room temperature under nitrogen atmosphere. The progress ofthe reaction was monitored using thin layer chromatography. The crudeproduct was isolated by pouring the reaction mixture into cold water andfiltering the solid precipitate. The pure product was isolated with 98%purity as white powder by crystallization using ethyl acetate solvent.The solid product was characterized using HPLC and NMR spectroscopy. Thepurified product (1) had a melting point of 73-75° C.

Example 2 Synthesis of Glycolic Acid Functionalized Adipic Acid

Into the flask of a Parr apparatus at room temperature was added withstirring 97 grams (219 mmol) of compound (1) in 400 ml of dry ethylacetate. Twenty grams of palladium on charcoal catalyst (50% wet) wasadded. The solution was maintained in hydrogen atmosphere under pressure(4 Kg/cm²) and was shaken overnight. The progress of the reaction wasmonitored using thin layer chromatography. The crude product wasisolated by filtering the catalyst and distilling off the ethyl acetateunder vacuum. The crude solid product was taken in hexane and filtered.The isolated solid crude product was purified via crystallization inethyl acetate. The pure product was isolated as white powder bycrystallization using ethyl acetate solvent. The pure product (2) wascharacterized using mass spectroscopy and NMR spectroscopy. The purifiedproduct had a melting point of 108-110° C.

Example 3 Synthesis of Glycolic Acid Functionalized HexamethyleneDiamine

Into an oven-dried 250 ml round-bottomed flask under a nitrogenatmosphere at room temperature were added with stifling 50 grams (430mmol) of hexamethylene diamine, 500 ml of ethyl acetate and 215 grams ofsodium bicarbonate. This stirring solution was placed in an ice bath atroom temperature. To this solution stirring at room temperature wasadded dropwise 75 ml of chloroacetyl chloride. The reaction mixture wasstirred overnight at in ice bath under nitrogen atmosphere. The progressof the reaction was monitored using thin layer chromatography. The crudeproduct was isolated by pouring the reaction mixture into cold water andfiltering the solid precipitate. The pure product was isolated with 98%purity as white powder by crystallization using a (80:20) mixture ofchloroform and methanol. The solid product was characterized using HPLCand NMR spectroscopy. The purified product had a melting point of130.7-132.4° C.

Example 4

Synthesis of Polyesteramide from Glycolic Acid FunctionalizedHexamethylene Diamine and Glycolic Acid Functionalized Adipic Acid

Into an oven-dried 250 ml round-bottomed flask under a nitrogenatmosphere at room temperature were added with stifling 10.00 grams ofg, 10.26 grams of in 50 ml of dimethylacetamide. The solution was heatedto 60° C. To this solution maintained at 60° C. was added dropwise 13.28ml of triethylamine and the reaction mixture was left for stirringovernight at the same temperature. The progress of the reaction wasmonitored by the observance of the triethylamine salt. The reactionmixture was left for stirring one more night at the same temperature(60° C.). After stirring the reaction mixture for two nights, 0.5 gramsof glycolic acid was further added to ensure that the polyesteramide endgroups are terminated with acid group. The reaction mixture was thenfurther left for stirring one more night. The crude product was isolatedby pouring the reaction mixture into cold water followed by extractionusing ethyl acetate. The final product (5) was isolated as a liquid bydistilling off the ethyl acetate solvent. The final liquid product (5)was characterized using HPLC and NMR spectroscopy.

Example 5 Synthesis of Polyesteramide

Preparation of the polyesteramide described in Example 4 was repeatedand the polymer solution was precipitated in cold water, and washed withIsopropyl alcohol several times followed by filtration and drying. Awhite powder (9 grams) with melting point of 83.5-87° C. was obtained.In vitro hydrolysis of 50 mg of this polyesteramide in 50 ml, pH 9buffer at 100° C., resulted in complete hydrolysis in about one hour.

Example 6 Synthesis of Polyesteramide

Preparation of the polyesteramide described in Example 4 was repeatedwithout addition of the chain terminator (glycolic acid), and thepolymer solution was precipitated in cold water, and washed withisopropyl alcohol several times followed by filtration and drying. Awhite powder (10 grams) with melting point of 105.5-108.5° C. wasobtained. In vitro hydrolysis of 50 mg of this polyesteramide in 50 ml,pH 9 buffer at 100° C., resulted in complete hydrolysis in about onehour.

Example 7 Synthesis of Hexamethylenediamine-Bisglycolate

Into a three-necked, oven-dried 250 ml round-bottomed flask equippedwith a short path distillation head, maintained under a nitrogenatmosphere at room temperature over a magnetic stirrer were added withstifling 11.6 grams of hexamethylenediamine and 25 grams of methylglycolate. This stifling solution was initially heated at 80° C. and thetemperature of the flask was raised to 120° C. within an hour to distilloff the methanol formed during the course of reaction. After thedistillation of methanol, the temperature of the flask was lowered backto room temperature. The residual crude product was purified byrecrystallization from methanol to yield 17.4 grams ofhexamethylenediamine-bisglycolate. The isolated solid was againrecrystallized from methanol to yield a purity level greater than 99%.The re-crystallized solid had a melting point of 127° C. as determinedby DSC (Differential Scanning calorimetry).

Example 8

Synthesis of Polyesteramide Consisting of two Glycolic Acid Units in thePolymer Repeat Unit, from Hexamethylenediamine Bis(Glycolate) andAdipoyl Chloride in Chlorobenzene (N66-2G Polymer)

Into a three-necked, oven-dried 250 ml round-bottomed flask equippedwith a dropping funnel and maintained under a nitrogen atmosphere atroom temperature were added with stifling 2.32 grams ofhexamethylenediamine bis(glycolate) in 150 ml of freshly distilledchlorobenzene. The reaction mixture was heated up to the refluxingtemperature. Into this reaction mixture was added a solution of 1.83grams of adipoyl chloride (dried over calcium sulfate) in 50 ml ofchlorobenzene. The reaction mixture was refluxed for 4 hours until theevolution of HCl ceased, accompanied by the formation of oil clinging tothe walls of the flask. The flask was cooled resulting in thesolidification of oil. The chlorobenzene solvent was removed, and wasfollowed by the addition of isopropanol and trifluoroethanol coupledwith refluxing and stifling for a week to remove the solid polymerformed from the walls of the flask. The polymer was characterized usingDSC and NMR spectroscopy in a mixture of CD₂Cl₂ containing 5 percent bywt of deuterated HFIP. The polymer was determined to have a glasstransition temperature of 20° C. and a melting temperature of 124° C.Films of the polymer were prepared on pre-weighed glass slides using a(˜10-20% weight/volume) solution of polymer in 2,2,2-trifluoro ethanol.Hydrolytic degradation studies of the polymer film in pH 7.4 buffermaintained at 50° C. for 24 hours resulted in approximately 3% weightloss as a result of hydrolysis.

Example 9

Synthesis of Polyesteramide Consisting of Four Glycolic Acid Units inthe Polymer Repeat Unit, from Hexamethylenediamine Bis(Diglycolate) andAdipoyl Chloride in Chlorobenzene (N66-4G Polymer)

Into a three-necked, oven-dried 250 ml round-bottomed flask equippedwith a dropping funnel and maintained under a nitrogen atmosphere atroom temperature were added with stifling 3.48 grams ofhexamethylenediamine bis(diglycolate) in 150 ml of freshly distilledchlorobenzene. The reaction mixture was heated up to 100° C. Into thisreaction mixture was rapidly added a solution of 1.83 grams of adipoylchloride (dried over calcium sulfate) in 50 ml of chlorobenzene. Thereaction mixture was left for stirring overnight at 100° C. The reactionmixture was then cooled and the chlorobenzene was decanted off. Theresidue was allowed to cool overnight to form an off-white solid thatwas recovered and removed from the flask using acetone. The solid wasthen filtered off and dried to yield 3.8 grams of polyesteramide havingfour glycolic acid moieties per repeating unit of the formed polymer.DSC studies revealed that the polymer has a glass transition temperatureof 17° C. and a melting temperature of 105° C. Films of the polymer wereprepared on pre-weighed glass slides using a (˜10-20% weight/volume)solution of polymer in 2,2,2-trifluoro ethanol. Hydrolytic degradationstudies of the polymer film in pH 7.4 buffer maintained at 50° C. for 24hours resulted in ≧95% weight loss as a result of hydrolysis.

Example 10

Hydrolytic Degradation Studies of Polyesteramides with Varying Number ofGlycolic Acid Units in the Polymer Repeat Unit

TABLE 1 Starting % % Weight of weight weight % weight Sample the filmloss loss loss 6 No. Sample (mg) 1 Day 2 Days Days 1 Films ofPolyesteramide containing 68.0 3.0 4.5 25.0 two glycolic acid units inthe polymer repeat unit (N66-2G polymer) (See Example 8) 2 Films ofPolyesteramide containing 67.0 95.0 100 — four glycolic acid units inthe polymer repeat unit (N66-4G polymer) (see Example 9)

In order to demonstrate the ability to alter the hydrolytic degradationrates of polyesteramides by modifying the number of hydroxy acidmoieties per repeating unit in the polymer, films of similar weight wereprepared on pre-weighed glass slides from the polymer of Example 8 andthe polymer of Example 9. The films were then placed in pH 7.4 buffermaintained at 50° C. for 1, 2, and 6 days as shown above in Table 1.Films of polyesteramide containing four glycolic acid units in thepolymer repeat units underwent ≧95% weight loss as a result ofhydrolysis in 1 day. In contrast, films of polyesteramide containing twoglycolic acid units in the polymer repeat units underwent onlyapproximately 3% weight loss as a result of hydrolysis in 1 day.Furthermore, the film containing polyesteramide having two glycolic acidunits in the polymer repeat units lost only 25% of its weight in 6 days.This experiment shows the ability to control hydrolytic degradation rateas a function of the number of glycolic acid units in the polymer repeatunit in accordance with the present invention.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. (canceled)
 2. A polyesteramide comprising Formula IV:—[—(X—O—)_(a)—C(═O)—R¹—C(═O)—(O—Y)_(b)—NH—R²—NH—]_(n)—  IV wherein: eachR¹ and R² is independently alkylene, cycloalkylenealkylene,arylenealkylene, arylenealkylenearylene,cycloalkylenealkylenecycloalkylene, or arylenealkylenecycloalkylene,wherein: (1) one or more of the —CH₂— moieties in the alkylene chainportion of an alkylene, cycloalkylenealkylene, arylenealkylene,arylenealkylenearylene, cycloalkylenealkylenecycloalkylene, orarylenealkylenecycloalkylene moiety are optionally replaced by —O— or—S—; or (2) one or more of the —CH₂—CH₂— moieties in the alkylene chainportion of an alkylene, cycloalkylenealkylene, arylenealkylene,arylenealkylenearylene, cycloalkylenealkylenecycloalkylene, orarylenealkylenecycloalkylene moiety are optionally replaced by —C(═O)—O—or —O—C(═O)—; each X is independently —C(═O)—CH(CH₃)—,—C(═O)—(CH₂)_(y)—, or —C(═O)—(CH₂CH₂O)_(Z)—CH₂—; each Y is independently—CH(CH₃)—C(═O)—, —(CH₂)_(y)—C(═O)—, or —(CH₂CH₂O)_(z)—CH₂—C(═O)—; each aand b is independently an integer from about 2 to about 6; each y and zis independently an integer from about 1 to about 24; and n is aninteger from about 5 to about
 5000. 3. A polyesteramide comprisingFormula VI:—[C(═O)—R¹—C(═O)—(O—Y¹)_(b)—NH—R²—NH—(X¹—I—)_(a)—]_(n)—;  VI wherein:each R¹ and R² is independently alkylene, cycloalkylenealkylene,arylenealkylene, arylenealkylenearylene,cycloalkylenealkylenecycloalkylene, or arylenealkylenecycloalkylene,wherein: (1) one or more of the —CH₂— moieties in the alkylene chainportion of an alkylene, cycloalkylenealkylene, arylenealkylene,arylenealkylenearylene, cycloalkylenealkylenecycloalkylene, orarylenealkylenecycloalkylene moiety are optionally replaced by —O— or—S—; or (2) one or more of the —CH₂—CH₂— moieties in the alkylene chainportion of an alkylene, cycloalkylenealkylene, arylenealkylene,arylenealkylenearylene, cycloalkylenealkylenecycloalkylene, orarylenealkylenecycloalkylene moiety are optionally replaced by —C(═O)—O—or —O—C(═O)—; each X¹ is independently —C(═O)—CH(CH₃)—,—C(═O)—(CH₂)_(y)—, or —C(═O)—(CH₂CH₂O)_(z)—CH₂—; each Y¹ isindependently —CH(CH₃)—C(═O)—, —(CH₂)_(y)—C(═O)—, or—(CH₂CH₂O)_(z)—CH₂—CH₂—C(═O)—; each a and b is independently an integerfrom about 1 to about 6; each y and z is independently an integer fromabout 1 to about 24; and n is an integer from about 5 to about
 5000. 4.A polyesteramide comprising Formula VIII:—[(X—O—)_(a)—C(═O)—R⁵—NH—(X¹—O—)_(a)—]_(n)—  VIII wherein: each R⁵ isindependently alkylene, cycloalkylenealkylene, arylenealkylene,arylenealkylenearylene, cycloalkylenealkylenecycloalkylene, orarylenealkylenecycloalkylene, wherein: (1) one or more of the —CH₂—moieties in the alkylene chain portion of an alkylene,cycloalkylenealkylene, arylenealkylene, arylenealkylenearylene,cycloalkylenealkylenecycloalkylene, or arylenealkylenecycloalkylenemoiety are optionally replaced by —O— or —S—; or (2) one or more of the—CH₂—CH₂— moieties in the alkylene chain portion of an alkylene,cycloalkylenealkylene, arylenealkylene, arylenealkylenearylene,cycloalkylenealkylenecycloalkylene, or arylenealkylenecycloalkylenemoiety are optionally replaced by —C(═O)—O— or —O—C(═O)—; each X and X¹is independently —C(═O)—CH(CH₃)—, —C(═O)—(CH₂)_(y)—, or—C(═O)—(CH₂CH₂O)_(z)—CH₂—; each a is independently an integer from about1 to about 6; each y and z is independently an integer from about 1 toabout 24; and n is an integer from about 5 to about
 5000. 5. (canceled)6. A polyesteramide comprising: a polymer wherein: one or more of theamido linkages in the polymer backbone are replaced with—[C(═O)—(O—X¹)_(a)—N]— linkages; or one or more of the ester linkages inthe polymer backbone are replaced with —[C(═O)—(O—X²)_(b)—O]— linkages;wherein: each X¹ and each X² is independently selected from:—CH(CH₃)—C(═O)—, —(CH₂)_(y)—C(═O)—and —(CH₂CH₂O)_(z)—CH₂—C(═O)—; andeach a and each b is independently an integer from 1 to about 24,provided that at least one a or at least one b is an integer from 2 toabout
 24. 7. A polyesteramide according to claim 6, wherein: one or moreof the amido linkages in the polymer backbone are replaced with—[C(═O)—(O—X¹)_(a)—N]— linkages; and one or more of the ester linkagesin the polymer backbone are replaced with —[C(═O)—(O—X²)_(b)—O]—linkages.
 8. A polyesteramide according to claim 6, wherein each a andeach b is independently an integer from 1 to about
 12. 9. Apolyesteramide according to claim 8, wherein each a and each b isindependently an integer from 1 to about
 6. 10. A polyesteramideaccording to claim 9, wherein each a and each b is independently aninteger from 1 to about
 3. 11. A surgical article comprising thepolyesteramide of claim
 2. 12. A surgical article of claim 11, whereinthe polyesteramide is further polymerized with a lactone monomer.
 13. Asurgical article of claim 12, wherein the lactone monomer is selectedfrom the group consisting of glycolide, lactide, ε-caprolactone,trimethylene carbonate, and p-dioxanone.
 14. A surgical article of claim11, wherein the article is a stent.
 15. A surgical article of claim 11,wherein the article is a scaffold for tissue engineering comprising aporous structure for the attachment and proliferation of cells.
 16. Acoating for a stent, comprising the polyesteramide of claim
 11. 17. Adrug delivery system, comprising the polyesteramide of claim 11physically in admixture with a biologically or pharmacologically activeagent.
 18. A drug delivery system of claim 17, wherein the biologicallyor pharmacologically active agent is physically embedded or dispersedinto the polymer and the polymer is in the form of a polymeric matrix.19. A surgical article of claim 11, wherein the article is a surgicalsuture.
 20. A surgical article of claim 11, wherein the article is anadhesion prevention barrier film.
 21. A surgical article of claim 11,wherein the article is a film, sheet, plate, clip, staple, pin, screw,or mesh.
 22. A biodegradable packaging material comprising thepolyesteramide of claim
 2. 23. A biodegradable packaging material ofclaim 22, wherein the polyesteramide has been further polymerized with alactone monomer selected from glycolide, lactide, ε-caprolactone,trimethylene carbonate, and p-dioxanone.
 24. (canceled)